This application deals with the central theme that vasoactive hormones, whether vasoconstrictors or dilators, have an action on the prostaglandin cascade either to modulate their action or as part of their vascular effects. In our new work on hyporeninemic hypoaldosteronism, we have preliminary data both in vivo and in vitro that the alternate pathways of arachidonic acid metabolism to prostacyclin are important in the mode of action of angiotensin and in the prostaglandin disorder underlying the hyporeninemic hypoaldoseronism syndrome. We postulate that this is due to vascular disease where arachidonic acid metabolism is shunted to 12 and 15 lipoxygenase products. We will measure 12-HETE in hyporeninemic hypoaldoseronism patients and compare this with both normals, diabetics, and with non hyporeninemic hypoaldoseronism renal disease patients. This study will use our validated 6 keto PGF and the new 12-HETE HPLC-RIA methodology. A trial of a longer acting PGI analogue, iloprost, under an IND will also be included. In the second project, we wish to determine whether dopamine acts on splanchnic vasculature in a manner resembling bradykinin, that is by activating prostacyclin probably via altered calcium flax. Strong preliminary data indicates that a low dose of dopamine which does not alter systemic Bp and is blocked by metaclopramide, both increases renal blood flow (PAH clearance) and increases prostacyclin excretion rate. These events are blocked by CO inhibitors or calcium channel blockers. This study will be extended by using a higher dose and a study of the effect of DA in moderate essential hypertensives to determine whether vascular prostaglandin responses are altered in hypertension. A subproject is designed to determine whether these effects are via DA or DA2 (DA plus domperidone or bromocriptine) receptor activation. Our third project is a series of in vitro studies of angiotensin feedback inhibition of renin release. We have evidence that 12 and 15- HETE are potent inhibitors of renin, and recent results on adrenal and vascular tissue suggest that All acts via the LO pathway. Using slices or enriched juxtaglomerular cell preparations in a perifusion set-up, we will study the effect of angiotensin on 12- HETE formation and on arachidonic acid metabolism, as well as the effect of various LO inhibitors on these events. This work is of fundamental importance, but also bears directly on the pathophysiology of diabetic vascular disease and the hyporeninemic hypoaldoseronism syndrome.